Prion Diseases

Proteinaceous infectious particles or prions

Prions induce conformational change ("misfolding") of normal brain protein (prion protein; PrP)

Prion disease can be hereditary, sporadic, and transmissible

Hereditary disorders cause

• Familial Creutzfeldt–Jakob disease (fCJD)

• Gerstmann-Sträussler-Scheinker syndrome (GSS)

• Fatal familial insomnia (FFI)

• PrP systemic amyloidosis

Sporadic Creutzfeldt-Jakob disease (sCJD)

• Accounts for approximately 85% of cases

• No known cause

Transmissible prion disease is only described for kuru and Creutzfeldt-Jakob disease in its iatrogenic (iCJD) and variant (vCJD) form

Iatrogenic transmission of CJD is associated with

• Prion contaminated human corneas

• Dura mater grafts

• Pituitary-derived growth hormone, gonadotropins

• Stereotactic electroencephalography electrodes and neurosurgical instruments

Kuru is now rare

vCJD (bovine spongiform encephalopathy [BSE] or "mad cow disease")

• Characterized by its bovine-to-human transmission through ingestion of meat from cattle infected with BSE

• There is no animal-to-animal spread of BSE and milk and its derived products are not considered to be infected

• Secondary transmission due to blood transfusions from asymptomatic donors are reported in the United Kingdom

• Rare in the United States; between 1996 and 2015, only 4 cases reported in the United States and 19 in Canada. Of the US reported cases, none acquired the disease locally (2 of them acquired the infection in the United Kingdom and 1 in Saudi Arabia).

Both sCJD and fCJD usually present in the sixth or seventh decade of life, whereas the iCJD form tends to occur in a much younger population

Clinical features of these three forms of disease usually involve

• Mental deterioration (dementia, behavioral changes, loss of cortical function) progressive over several months

• Myoclonus

• Extrapyramidal (hypokinesia) and cerebellar manifestations (ataxia, dysarthria)

Finally, coma ensues, usually associated with an akinetic state and less commonly decerebrate/decorticate posturing

Kuru

• Early stage of tremors, ataxia and postural instability followed by involuntary movements (myoclonus, fasciculations and choreathetosis)

• Final stage of dementia

GSS

• Rare inherited autosomal dominant (rarely sporadic) disorder that occurs in kindred

• Typically causes a disruption of the circadian sleep-activity pattern leading to insomnia, hallucinations, behavioral changes, motor disturbance and rarely dementia

FFI is the only prior disease associated with endocrine disorders and dysautonomia

Detection of 14-3-3 protein in the cerebrospinal fluid is helpful for the diagnosis of sCJD but not in vCJD and fCJD

A blood-based assay and a polymerase chain reaction (PCR) in cerebrospinal fluid show some promising results in the diagnosis of vCJD with high specificity but 71% sensitivity; further evaluation is under way

EEG

• In CJD, typically shows a pattern of paroxysms with high voltages and slow waves

• In sCJD, typically shows a pattern of paroxysms with high voltages and slow waves

• In vCJD, is diffusely abnormal but nondiagnostic

MRI

• In CJD, is characteristic for bilateral areas of increased signal intensity, predominantly in the caudate and putamen

• In sCJD,

  • Bilateral areas of increased signal intensity, predominantly in the caudate and putamen, are characteristic

  • Diagnostic sensitivity increases to 91% when an experienced neuroradiologist or prion disease expert reviews the MRI

• In vCJD, characteristically reveals hyperintensity of the posterior thalamus ("pulvinar sign")

Positron emission tomography can help distinguish GSS disease

Probable diagnosis requires the presence of rapidly progressive dementia plus two of four clinical features (myoclonus, visual or cerebellar signs, pyramidal/extrapyramidal signs, and akinetic mutism) as well as a positive laboratory assay (typical EEG, positive 14-3-3 CSF assay with duration under 2 years

Differentiation and definitive diagnosis of these neurodegenerative diseases are ultimately established by neuropathologic confirmation

No specific therapy available

Flupirtine (an analgesic drug) is sometimes useful in slowing the associated cognitive decline but does not affect survival